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WO1996037509A1 - Agents antifongiques a peptides cycliques - Google Patents

Agents antifongiques a peptides cycliques Download PDF

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Publication number
WO1996037509A1
WO1996037509A1 PCT/US1996/007243 US9607243W WO9637509A1 WO 1996037509 A1 WO1996037509 A1 WO 1996037509A1 US 9607243 W US9607243 W US 9607243W WO 9637509 A1 WO9637509 A1 WO 9637509A1
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Prior art keywords
compound
hydroxy
formula
alkyl
methyl
Prior art date
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PCT/US1996/007243
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English (en)
Inventor
Peter S. Borromeo
William W. Turner
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to AU57990/96A priority Critical patent/AU5799096A/en
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Publication of WO1996037509A1 publication Critical patent/WO1996037509A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/27—Cyclic peptide or cyclic protein

Definitions

  • This invention relates to semi-synthetic cyclic peptide compounds which are useful as antifungal and antiparasitic agents and which have improved stability and water solubility.
  • it relates to derivatives of the echinocandin class of cyclic peptides, to methods for treating fungal and parasitic infections, and to formulations useful in the methods.
  • the compounds provided by this invention are semi-synthetic compounds derived from cyclic peptides which are produced by culturing various microorganisms.
  • a number of cyclic peptides are known in the art including
  • echinocandin B (A30912A), aculeacin, mulundocandin, sporiofungin, L-671,329, and S31794/F1.
  • these cyclic peptides may be structurally characterized as a cyclic hexapeptide core (or nucleus) with an acylated amino group on one of the core amino acids.
  • the amino group is typically acylated with a fatty acid group forming a side chain off the nucleus.
  • echinocandin B has a linoleoyl side chain while aculeacin has a palmitoyl side chain.
  • the fatty acid side chains may be removed from the cyclic peptide core to provide an amino nucleus (for example, a compound of formula I, below, where R 2 is hydrogen).
  • the amino group may then be re-acylated to provide semi-synthetic compounds such as those claimed in the present application.
  • the echinocandin B nucleus has been re-acylated with certain non-naturally occurring side chain moieties to provide a number of antifungal agents (see, Debono, U.S. Pat. Ser. No. 4,293,489).
  • antifungal agents is cilofungin which is represented by a compound of formula IA where R', R" and R'" are methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and R 2 is p-(octyloxy)benzoyl.
  • the present invention provides a compound of formula IA where R', R" and R'" are methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and R 2 is p-(octyloxy)benzoyl.
  • R' is hydrogen, methyl or -CH 2 C(O)NH 2 ;
  • R" and R'" are independently methyl or hydrogen;
  • R x1 is hydrogen, hydroxy or -O-R;
  • R is C 1 -C 6 alkyl, benzyl, -(CH 2 ) 2 Si(CH 3 ) 3 ,
  • a, b and c are independently 1, 2, 3, 4, 5 or 6;
  • R z1 and R z2 are independently hydrogen, C 1 -C 6 alkyl, or R z1 and R z2 combine to form -CH 2 (CH 2 ) e CH 2 -;
  • R z3 and R z4 are independently hydroxy or C 1 -C 6 alkoxy
  • d is 1 or 2;
  • e 1, 2 or 3;
  • R x2 , R y1 , R y2 , R y3 and R y4 are independently hydroxy or hydrogen;
  • R 0 is hydroxy, -OP(O)(OH) 2 or a group of the formulae:
  • R 1 is C 1 -C 6 alkyl, phenyl, p-halo-phenyl, p-nitrophenyl, benzyl, p-halo-benzyl or p-nitro-benzyl;
  • each R 2a is independently hydroxy, halo, nitro, amino, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or
  • a 1, 2, 3 or 4;
  • R 3 is C 1 -C 12 alkyl, C 1 -C 12 alkoxy or
  • n 2, 3 or 4;
  • n 2, 3 or 4;
  • p is 0 or 1;
  • compositions for inhibiting parasitic or fungal activity and methods of treating fungal or parasitic infections which employ the compounds of the invention.
  • C 1 -C 12 alkyl refers to a straight or branched alkyl chain having from one to twelve carbon atoms.
  • Typical C 1 -C 12 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t- butyl, pentyl, 5-methylpentyl, hexyl, heptyl, 3,3- dimethylheptyl, octyl, 2-methyl-octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • C 1 -C 12 alkyl includes within its definition the terms "C 1 -C 6 alkyl” and C 1 -C 4 alkyl.”
  • halo refers to chloro, fluoro, bromo or iodo.
  • C 1 -C 12 alkylthio refers to a straight or branched alkyl chain having from one to twelve carbon atoms attached to a sulfur atom.
  • Typical C 1 -C 12 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, 3-methyl-heptylthio, octylthio, 5, 5-dimethyl-hexylthio and the like.
  • C 1 -C 12 alkoxy refers to a straight or branched alkyl chain having from one to twelve carbon atoms attached to an oxygen atom.
  • Typical C 1 -C 12 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, sec-butoxy, pentoxy, 5-methyl-hexoxy, heptoxy, octyloxy, decyloxy dodecyloxy and the like.
  • C 1 -C 12 alkyl includes within its definition the terms "C 1 -C 6 alkoxy” and C 1 -C 4 alkoxy.”
  • hydroxy protecting group refers to a substituent of an hydroxy group that is commonly employed to block or protect the hydroxy functionality while reactions are carried out on other functional groups on the compound.
  • hydroxy protecting groups include tetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth- 1-yl, methoxymethyl, ⁇ -methoxyethoxymethyl, methylthio- methyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'- dimethoxytrityl, 4, 4', 4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, trimethylsilylethyl, (t-butyl) dimethyl- silyl, and 2,2,2-trichloroethoxycarbonyl and the like.
  • the species of hydroxy protecting group is not critical so long as the derivatized hydroxy group is stable to the
  • a preferred hydroxy protecting group is trimethylsilylethyl. Further examples of hydroxy
  • protected hydroxy refers to a hydroxy group bonded to one of the above hydroxy protecting groups.
  • amino protecting group refers to substituents of the amino group commonly employed to block or protect the amino
  • amino protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl groups, or urethane-type blocking groups such as benzyloxycarbonyl, 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4- chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 3 -bromobenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t- butoxycarbonyl, 2-(4-xenyl)isopropyl, urethane-type blocking groups such as
  • amino protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction (s) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino protecting group (s).
  • Preferred amino protecting groups are t-butoxycarbonyl (t-Boc),
  • inhibiting i.e. a method of inhibiting parasitic or fungal activity, includes stopping, retarding or prophylactically hindering or preventing the growth or any attending characteristics and results from the existence of a parasite or fungus.
  • contacting i.e. contacting a compound of the invention with a parasite or fungus
  • contacting includes a union or junction, or apparent touching or mutual tangency of a compound of the invention with a parasite or fungus.
  • the term does not imply any further limitations to the process, such as by mechanism of inhibition, and the methods are defined to encompass the spirit of the invention, which is to inhibit parasitic and fungal activity by the action of the compounds and their inherent antiparasitic and antifungal properties, or in other words, the compounds, used in the claimed methods are the causative agent for such inhibition.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are mineral acids such as hydrochloric acid,
  • hydrobromic acid hydroiodic acid, sulfuric acid
  • organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
  • phenylbutyrate citrate, lactate, ⁇ -hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate,
  • acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium
  • potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • Preferred compounds of this invention are those compounds of formula I where:
  • R', R" and R'" are each methyl
  • R y1 , R y2 , R y3 and R y4 are each hydroxy;
  • R x1 is hydrogen, hydroxy or -O-R;
  • R is methyl, benzyl, -CH 2 CHOHCH 2 OH, - (CH 2 ) b NR z1 R z2 or - (CH 2 )2POR z3 R z4 ;
  • b is 2, 3, 4, 5 or 6;
  • R z1 and R z2 are independently hydrogen or C 1 -C 4 alkyl
  • R z3 and R z4 are independently hydroxy or methoxy,-
  • R x2 is hydrogen or hydroxy
  • R 0 is hydroxy, -OP(O)(OH) 2 or a group of the formulae:
  • R 1 is methyl
  • R x1 is hydrogen or hydroxy
  • R x2 is hydrogen or hydroxy
  • R 0 is hydroxy
  • a is 1 or 2;
  • R 2a is halo, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; and R 3 is C 1 -C 12 alkoxy or -O-(CH 2 ) 2 -O-(C 1 -C 12 alkyl); or a pharmaceutically acceptable salt thereof.
  • R x1 is hydroxy
  • R x2 is hydroxy
  • a 1;
  • R 2a is methyl, chloro, fluoro or methoxy
  • R 3 is C 1 -C 6 alkoxy
  • R 2a is methyl, chloro or fluoro
  • the compounds of formula I may be prepared according to Reaction Scheme I, as follows.
  • R nat is a naturally occurring cyclic peptide sidechain
  • R', R", R'", R x1 , R x2 , R y1 , R y2 , R y3 , R y4 , R 0 and R 2 are as defined above.
  • Reaction scheme I is accomplished by carrying out reactions A and B, above.
  • the intermediate compound may be isolated by procedures well-known in the art, for example, the compound may be crystallized or precipitated and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation.
  • the intermediate compound may be further purified, if desired, by common techniques such as crystallization or precipitation or chromatography over solid supports such as silica gel, alumina and the like, before carrying out the next step of the reaction scheme.
  • reaction IA a naturally occurring cyclic peptide of the formula IA is deacylated using procedures known in the art to provide an amino nucleus of formula IB.
  • This reaction is typically carried out using enzymatic deacylation by exposing the naturally occurring cyclic peptide to a deacylase enzyme.
  • the deacylase enzyme may be obtained from the microorganism Actinoplanes utahensis and used substantially as described in U.S. Patent Nos.
  • deacylase enzyme may also be obtained from the
  • Deacylation may be accomplished using whole cells of Actinoplanes utahensis or Pseudomonas or the crude or purified enzyme thereof or using an immobilized form of the enzyme. See European Patent Application No. 0 460 882 (December 11, 1991). Examples of naturally
  • cyclic peptides which may be used as starting materials include aculeacin (palmitoyl side chain), tetrahydroechinocandin B (stearoyl side chain),
  • a preferred naturally occurring cyclic peptide is echinocandin B (a compound of formula IA where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and R 2 is
  • Reaction IB the amino nucleus of formula IB is then re-acylated using procedures known in the art to provide a compound of formula I where R 0 is hydroxy; R x1 is hydroxy; and R 2 is an acyl group as defined hereinabove.
  • the amino nucleus may be acylated by reaction with an appropriately substituted acyl halide, preferably in the presence of an acid scavenger such as a tertiary amine, such as triethylamine.
  • an acid scavenger such as a tertiary amine, such as triethylamine.
  • the reaction is typically carried out at a temperature of from about -20°C to about 25°C.
  • Typical solvents for this reaction include polar aprotic solvents such as dioxane or
  • Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
  • the amino nucleus may also be acylated by reaction with an appropriately substituted carboxylic acid, in the presence of a coupling agent.
  • Typical coupling agents include dicyclohexylcarbodiimide (DCC), N,N'- carbonyldi-imidazole, bis (2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (EEDQ), benzotriazol-1-yloxytripyrro- lidinophosphonium hexafluorophosphate (PyBOP) and the like.
  • DCC dicyclohexylcarbodiimide
  • BOP-Cl bis (2-oxo-3-oxazolidinyl)phosphinic chloride
  • EEDQ N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline
  • PyBOP benzotriazol-1-y
  • the amino nucleus may be acylated with an activated ester of a carboxylic acid such as an ester of a carboxylic acid of the formula R 2 -COOH and p- nitrophenyl, 2,4,5-trichlorophenyl, hydroxybenzotriazole hydrate (HOBT ⁇ H 2 O), pentafluorophenol, N-hydroxysuccinimide and the like.
  • Preferred acylating moieties are the active esters of the carboxylic acid R 2 -COOH such as a
  • the reaction is typically carried out for one to sixty five hours at a temperature from about 0°C to about 30°C in an aprotic solvent.
  • the reaction is generally complete after about twenty four to forty eight hours when carried out a temperature of from about 15°C to about 30°C.
  • Typical solvents for this reaction are
  • amino nucleus is generally employed in equimolar proportions relative to the activated ester or with a slight excess of the amino nucleus.
  • R x1 is hydroxy
  • R x1 is -O-R, where R is C 1 -C 6 alkyl, benzyl,
  • reaction is typically carried out in a polar aprotic solvent such as dioxane or dimethylsulfoxide at a temperature of from about 0°C to about 35°C, preferably at about room temperature. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired
  • Preferred acids include p-toluenesulfonic acid, hydrochloric acid and camphorsulfonic acid.
  • Suitable catalysts include N- methylmorpholine N-oxide (NMO) and the like.
  • Typical solvents suitable for use in this reaction include
  • Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired
  • the reaction is preferably conducted at a temperature in the range of from about 20°C to about 30°C for about eighteen to twenty four hours.
  • the compounds of formula I where R 0 is hydroxy may be phosphorylated by reaction with an appropriately substituted alkyl or phenyl phosphate to provide a compound of formula I where R 0 is -O-P(O)OH-R 1 where R 1 is C 1 -C 6 alkoxy or phenoxy, or by reaction with an appropriately substituted alkyl or phenyl phosphonic acid to provide a compound of formula I where R 0 is -O-P(O)OH-R 1 where R 1 is C 1 -C 6 alkyl, or an appropriately substituted phenyl or benzyl moiety, to provide a compound of formula I where R 0 is a group of the formula -OP(O)OH-R 1 .
  • the phosphonic acid is typically used in an activated form, for example as a phosphonic halide, preferably a phosphonic chloride.
  • the reaction is carried out in the presence of a base such as lithium trimethylsilanolate (LiOTMS), lithium
  • the reaction is typically carried out for up to one hour at a temperature from about -30°C to about 0°C in an aprotic solvent such as tetrahydrofuran and dimethylformamide.
  • the reaction is generally complete in about fifteen minutes when carried out under these conditions.
  • the phosphate or phosphonate reactant is generally employed in equimolar proportions to about a one mole excess relative to the amino nucleus in the presence of an equimolar or slight excess of the base.
  • Phosphorylation of an amino nucleus with unprotected aminal hydroxy groups is typically carried out at lower temperatures, for example from about -30°C to about -15°C.
  • aminal hydroxy moieties on the compound of formula I are optionally protected with an hydroxy protecting group using procedures known in the art.
  • the reaction is typically carried out by combining the compound of formula I with a suitable hydroxy protecting group in the presence of a catalyst at a
  • hydroxy protecting group is generally employed in an amount ranging from about equimolar proportions to about a 100 molar excess relative to the compound of formula I, preferably in a large molar excess.
  • Suitable catalysts include strong acids such as p-toluenesulfonic acid, camphorsulfonic acid (CSA), hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like.
  • Typical solvents suitable for use in this reaction include any organic solvent such as dioxane.
  • Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
  • the reaction is preferably conducted at a temperature in the range of from about 20°C to about 30°C for about two to four hours.
  • the protected compound of formula I is then phosphorylated as described above.
  • the hydroxy protecting group (s) are then removed according to procedures known in the art to provide a phosphorylated compound of formula I.
  • the protecting groups can be removed by reaction with a Lewis acid in a mutual inert organic solvent such as methylene chloride. Examples of Lewis acids include
  • reaction is typically carried out at a
  • Lewis acid is boron trifluoride etherate.
  • the dideoxy compounds of formula I are prepared by removing the benzylic and aminal hydroxy groups (R x2 and R x1 , respectively).
  • the hydroxy groups may be removed by subjecting a non-dideoxy compound of formula I (where R 2 is hydrogen or acyl) to a strong acid and a reducing agent at a temperature of between -5°C and 70°C, in a suitable solvent.
  • Typical strong acids include trichloroacetic acid, trifluoroacetic acid or borontrifluoride etherate. A preferred strong acid is trifluoroacetic acid.
  • Typical reducing agents include sodium cyanoborohydride or
  • triethylsilane A preferred reducing agent is triethylsilane.
  • Suitable solvents include methylene chloride, chloroform or acetic acid, preferably methylene chloride.
  • the strong acid should be present in an amount of from 2 to 80 mol per mol of substrate, and the reducing agent should be present in an amount of 2 to 80 mol per mol of substrate. This process affords selective removal of the aminal and benzylic hydroxy groups.
  • the cyclic peptides used to make the compounds of the present invention may be prepared by fermentation of known microorganisms.
  • the cyclic peptide of formula IB where R', R" and R'" are methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy (cyclic nucleus corresponding to A-30912A) may be prepared using the procedure detailed in Abbott et al., U.S. Pat. Ser. No. 4,293,482, which is herein incorporated by reference.
  • the cyclic peptide of formula IB where R', R" and R'" are methyl, R x1 is hydroxy, R x2 is hydrogen, R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy (cyclic nucleus corresponding to A- 30912B) may be prepared using the procedure detailed in
  • cyclic peptide of formula IB where R' is -CH 2 C(O)NH 2 , R" is methyl, R'" is hydrogen, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy may be prepared by deacylating the cyclic peptide prepared using the procedure detailed in Chen et al., U.S. Pat. Ser. No. 5,198,421, which is herein incorporated by reference.
  • the R 2 -COOH precursor acids are prepared by reacting an appropriately substituted biphenyl boronic acid reactant with an appropriately substituted p-halobenzoic acid reactant in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium and an inorganic base such as potassium carbonate.
  • a catalyst such as tetrakis (triphenylphosphine) palladium
  • an inorganic base such as potassium carbonate.
  • the reaction is typically carried out with equimolar proportions of the boronic acid reactant and the p-benzoic acid reactant, or a slight molar excess of the benzoic acid reactant relative to the boronic acid reactant, and a 1-2 molar excess of the inorganic base in a mutual inert organic solvent such as toluene at a temperature of from about 20°C to the reflux temperature of the reaction mixture.
  • the reaction is generally complete after about four to about ten hours when carried out at reflux temperature in toluene.
  • the boronic acid reactant may be prepared by reacting an appropriately substituted halobiphenyl reactant with two equivalents of triisopropyl borate in the presence of a slight molar excess of an alkyl lithium, for example sec-butyl lithium, relative to the halobiphenyl reactant in a mutual inert solvent such as tetrahydrofuran.
  • the alkyl lithium is typically combined with the solvent by dropwise addition at reduced temperatures ( ⁇ -70°C) and allowed to stir for approximately thirty minutes before the addition of the triisopropyl borate.
  • the reaction is typically carried out initially at a temperature of from about -100°C to about -50°C, preferably from about -75°C to about -85°C for thirty minutes to two hours and then warmed to room temperature and reacted for an additional one to three hours.
  • the reaction is generally complete in from several minutes to about four hours.
  • the boronic acid moiety is formed by the addition of an acid.
  • a preferred acid is a 1N hydrochloric acid solution.
  • the resultant carboxylic acid is then converted to an activated ester, preferably a benzotriazole ester, which is used to acylate the cyclic peptide nucleus as described above.
  • an activated ester preferably a benzotriazole ester
  • the carboxylic acid may be converted to the corresponding benzotrizole ester by combining the carboxylic acid with N-methanesulfonate- benzotriazole in a mutual inert solvent such as
  • absorption maxima listed for the IR spectra are only those of interest and not all of the maxima observed.
  • the desired titled compound was prepared substantially in accordance with the procedure detailed in Preparation 8B.
  • the desired titled compound was prepared substantially in accordance with the procedure detailed in Preparation 8B.
  • the desired titled compound was prepared substantially in accordance with the procedure detailed in Preparation 8B.
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 -, R y3 -, R y4 and R 0 are each hvdroxy and
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2, R y3 , R y4 and R 0 are each hydroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy), 0.68 g (1.38 mmol) of the compound of Preparation 4 in 120 ml of dimethylformamide. Yield: 0.9 g. High Res. MS (FAB) for C 59 H 76 N 7 O 17 :
  • R', R" and R'" are each methyl, R x1 , R x2 -, R y1 .
  • R y2 -, R y3 R y4 and R 0 are each hvdroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R° is hydroxy), 0.68 g (1.38 mmol) of the compound of Preparation 5 in 120 ml of dimethylformamide. Yield: 0.85 g.
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy), 0.7 g (1.37 mmol) of the compound of Preparation 6 in 100 ml of dimethylformamide. Yield: 0.9 g.
  • R'. R" and R'" are each methyl.
  • R x1 , R x2 , R y1 , R y2 , R y3 , R Y4 and R 0 are each hydroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 300 mg (0.37 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R"' are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy), 200 mg (0.37 mmol) of the compound of Preparation 7 in 35 ml of dimethylformamide. Yield: 310 mg.
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy), 0.79 g (1.44 mmol) of the compound of Preparation 8C in 50 ml of dimethylformamide. Yield: 1 g.
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R"' are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy), 0.73 g (1.44 mmol) of the compound of Preparation 9 in 50 ml of dimethylformamide. Yield: 1 g.
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hvdroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 1, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy), 0.79 g (1.44 mmol) of the compound of Preparation 10 in 50 ml of dimethylformamide to provide 0.8 g of crude material. This material was purified using HPLC (eluent of 45% acetonitrile in water) to provide 525 mg of the desired titled compound.
  • HPLC eluent of 45% acetonitrile in water
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and
  • hydroxybenzotriazole hydrate HOBT ⁇ H 2 O
  • DCC dicyclohexylcarbodiimide
  • R x1 , R x2 , R y1 , R y2 -, R y3 , R y4 and R 0 are each hvdroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 9, using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R"' are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R 0 is hydroxy) and 0.76 g (0.72 g actual, 1.38 mmol) of a solid [formed from a mixture containing 2.7 g (6.7 mmol) of the compound of Preparation 12, 1.65 g (8 mmol) of DCC and 1.23 g (8 mmol) of HOBT - H 2 O in 250 ml of methylene chloride] in 50 ml of dimethylformamide.
  • R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 , R y4 and R 0 are each hydroxy and
  • the titled compound was prepared substantially in accordance with the procedure detailed in Example 9 , using 1 g (1.25 mmol) of the compound of the (A-30912A) nucleus (compound of formula IB where R', R" and R'" are each methyl, R x1 , R x2 , R y1 , R y2 , R y3 and R y4 are each hydroxy and R° is hydroxy) and 0.72 g (0.68 g actual, 1.38 mmol) of a solid [formed from a mixture containing 1.8 g (4.76 mmol) of the compound of Preparation 11, 1.2 g (5.7 mmol) of DCC and 0.87 g (5.7 mmol) of HOBT ⁇ 2 O in 250 ml of methylene chloride] in 50 ml of dimethylformamide.
  • the compounds of formula I exhibit antifungal and antiparasitic activity.
  • the compounds of formula I inhibit the growth of various infectious fungi including Candida spp . such as C. albicans,
  • Aspergillus spp . such as A. fumigatus; Histoplasma spp . such as H. capsulatum; Cryptococcus spp . such as
  • Antifungal activity of a test compound was determined in vitro by obtaining the minimum inhibitory concentration (MIC) of the compound using a standard agar dilution test or a disc-diffusion test. The compound was then tested in vivo (in mice) to determine the effective dose of the test compound for controlling a systemic fungal infection.
  • MIC minimum inhibitory concentration
  • the compounds of the invention also inhibit the growth of certain organisms primarily responsible for opportunistic infections in immunosuppressed individuals.
  • the compounds of the invention inhibit the growth of Pneumocvstis carinii the causative organism of pneumocystis pneumonia (PCP) in AIDS and other
  • the compounds of formula I are active in vitro and in vivo and are useful in combating either systemic fungal infections or fungalskin infections. Accordingly, the present invention provides a method of inhibiting fungal activity comprising contacting a compound of formula I, or a pharmaceutically acceptable salt thereof, with a fungus. A preferred method includes inhibiting Candida albicans or Aspergillus fumigatis activity. The present invention further provides a method of treating a fungal infection which comprises administering an effective amount of a compound of formula I, or a pharmaceutically
  • a preferred method includes treating a Candida albicans or Aspergillus fumigatis infection.
  • the term "effective amount,” means an amount of a compound of the present invention which is capable of inhibiting fungal activity.
  • the dose administered will vary depending on such factors as the nature and severity of the infection, the age and general health of the host and the tolerance of the host to the antifungal agent.
  • the particular dose regimen likewise may vary according to such factors and may be given in a single daily dose or in multiple doses during the day. The regimen may last from about 2-3 days to about 2-3 weeks or longer.
  • a typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 100 mg/kg of body weight of an active compound of this invention.
  • Preferred daily doses generally will be from about 0.1 mg/kg to about 60 mg/kg and ideally from about 2.5 mg/kg to about 40 mg/kg.
  • the present invention also provides
  • the present invention also provides a pharmaceutical
  • formulation comprising one or more pharmaceutically
  • compositions comprising from 0.1% to 99.9% by weight of the formulation, more generally from about 10% to about 30% by weight.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with the other
  • ingredients of the formulation and not deleterious to the recipient thereof.
  • a compound of formula I may be administered parenterally, for example using intramuscular, sub- cutaneous, or intra-peritoneal injection, nasal, or oral means. In addition to these methods of administration, a compound of formula I may be applied topically for skin infections.
  • the formulation comprises a compound of formula I and a physiologically acceptable diluent such as deionized water, physiological saline, 5% dextrose and other commonly used diluents.
  • a physiologically acceptable diluent such as deionized water, physiological saline, 5% dextrose and other commonly used diluents.
  • the formulation may contain a solubilizing agent such as a polyethylene glycol or polypropylene glycol or other known solubilizing agent.
  • Such formulations may be made up in sterile vials containing the antifungal and excipient in a dry powder or lyophilized powder form.
  • a physiologically acceptable diluent Prior to use, a physiologically acceptable diluent is added and the solution withdrawn via syringe for administration to the patient.
  • compositions of the present invention are prepared by known procedures using known and readily available ingredients.
  • the active ingredient will generally be admixed with a carrier, or diluted by a carrier, or
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,
  • solutions syrups, aerosols, (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.
  • the antifungal compound is filled into gelatin capsules or formed into tablets. Such tablets may also contain a binding agent, a dispersant or other suitable excipients suitable for preparing a proper size tablet for the dosage and particular antifungal compound of the formula I.
  • the antifungal compound may be formulated into a flavored liquid suspension, solution or emulsion.
  • a preferred oral formulation is linoleic acid, cremophor RH-60 and water and preferably in the amount (by volume) of 8% linoleic acid, 5% cremophor RH-60, 87%s terile water and a compound of formula I in an amount of from about 2.5 to about 40 mg/ml.
  • the antifungal compound may be formulated with a dry powder for application to theskinsurface or it may be formulated in a liquid formulation comprising a solubilizing aqueous liquid or non-aqueous liquid, e.g., an alcohol or glycol.
  • active ingredient means a compound according to formula I or a
  • Hard gelatin capsules are prepared using the following ingredients:
  • a tablet is prepared using the ingredients below:
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • An aerosol solution is prepared containing the following components:
  • the active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed
  • the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • the active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose andsyrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • the solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.
  • the present invention further provides a method for treating or preventing the onset of Pneumocystis pneumonia in a host susceptible to Pneumocystis pneumonia which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a host in need ofsuch treatment.
  • the compounds of formula I can be used prophylactically to prevent the onset of the infection which is caused by the organism Pneumocystis carinii, or alternatively they can be used to treat a host that has been infected with P.
  • a compound of formula I may be administered parenterally, for example using intramuscular, intravenous or intra-peritoneal injection, orally or by inhaling directly into the airways of the lungs.
  • a preferred mode of administration is inhalation of an aerosol spray
  • an effective amount means an amount of a compound of the present invention which is capable of inhibiting parasitic activity.
  • An effective amount of the compound of formula I is from about 3 mg/kg of patient body weight to about 100 mg/kg.
  • the amount administered may be in a single daily dose or multiple doses of, for example, two, three or four times daily throughout the treatment regimen.
  • the amount of the individual doses, the route of delivery, the frequency of dosing and the term of therapy will vary according to such factors as the intensity and extent of infection, the age and general health of the patient, the response of the patient to therapy and how well the patient tolerates the drug. It is known that Pneumocystis
  • pneumonia infections in AIDS patients are highly refractory owing to the nature of the infection.
  • advanced infections the lumenal surface of the air passages becomes clogged with infectious matter and extensive parasite development occurs in lung tissue.
  • a patient with an advanced infection will accordingly require higher doses for longer periods of time.
  • immune deficient patients who are not severely infected and who are susceptible to Pneumocystis pneumonia can be treated with lower and less frequent prophylactic doses.

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  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne des compositions pharmaceutiques ainsi que des procédés d'inhibition d'activité fongique et parasitaire faisant appel à des composés correspondant à la formule (I) où R', R'', R''', R?x1, Rx2, Ry1, Ry2, Ry3, Ry4, et R0¿ sont tels que définis dans la description; R2 correspond à (II); chaque R2a est indépendamment hydroxy, halo, nitro, amino, trifluorométhyle, alkyle C¿1?-C6, alcoxy C1-C6 ou alkylthio C1-C6; a vaut 1, 2, 3 ou 4; R?3¿ est alkyle C¿1?-C12, alcoxy C1-C12 ou -O-(CH2)m-[O-(CH2)n]p-O-(alkyle C1-C12); m vaut 2, 3 ou 4; n vaut 2, 3 ou 4; et p vaut 0 ou 1. Cette invention concerne également les sels de ces composés, acceptables sur le plan pharmaceutique.
PCT/US1996/007243 1995-05-26 1996-05-20 Agents antifongiques a peptides cycliques Ceased WO1996037509A1 (fr)

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US6506726B1 (en) 1998-12-09 2003-01-14 Eli Lilly And Company Purification of Echinocandin cyclopeptide compounds
US6590073B2 (en) 1999-03-03 2003-07-08 Eli Lilly And Company Formation and anion-exchange of crystalline echinocandin ammonium salts
US6653281B1 (en) 1998-08-20 2003-11-25 Eli Lilly And Company Ring modified cyclic peptide analogs
US6670324B2 (en) 1998-02-25 2003-12-30 Eli Lilly And Company Cyclic peptide antifungal agents
US6821951B2 (en) 1999-03-03 2004-11-23 Eli Lilly And Company Processes for making pharmaceutical oral ECB formulations and compositions
US6960564B2 (en) 1999-03-03 2005-11-01 Eli Lilly And Company Echinocandin pharmaceutical formulations containing micelle-forming surfactants
US6991800B2 (en) 2002-06-13 2006-01-31 Vicuron Pharmaceuticals Inc. Antifungal parenteral products
US7041637B2 (en) 1999-03-03 2006-05-09 Eli Lilly And Company Echinocandin/carbohydrate complexes

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US6743777B1 (en) * 1992-03-19 2004-06-01 Eli Lilly And Company Cyclic peptide antifungal agents and process for preparation thereof
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JP2004536034A (ja) 2001-01-08 2004-12-02 ネオルクス コーポレイション 治療的および診断的化合物、組成物および方法
US7045116B2 (en) 2001-12-13 2006-05-16 Dow Global Technologies Inc. Treatment of osteomyelitis with radiopharmaceuticals
AU2004236248A1 (en) * 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Phenyl substituted carboxylic acids
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US6670324B2 (en) 1998-02-25 2003-12-30 Eli Lilly And Company Cyclic peptide antifungal agents
US6653281B1 (en) 1998-08-20 2003-11-25 Eli Lilly And Company Ring modified cyclic peptide analogs
US6939946B2 (en) 1998-08-20 2005-09-06 Eli Lilly And Company Ring modified cyclic peptide analogs
US6506726B1 (en) 1998-12-09 2003-01-14 Eli Lilly And Company Purification of Echinocandin cyclopeptide compounds
US6590073B2 (en) 1999-03-03 2003-07-08 Eli Lilly And Company Formation and anion-exchange of crystalline echinocandin ammonium salts
US6821951B2 (en) 1999-03-03 2004-11-23 Eli Lilly And Company Processes for making pharmaceutical oral ECB formulations and compositions
US6960564B2 (en) 1999-03-03 2005-11-01 Eli Lilly And Company Echinocandin pharmaceutical formulations containing micelle-forming surfactants
US7041637B2 (en) 1999-03-03 2006-05-09 Eli Lilly And Company Echinocandin/carbohydrate complexes
US7550428B2 (en) 1999-03-03 2009-06-23 Eli Lilly And Company Echinocandin/carbohydrate complexes
US8022033B2 (en) 1999-03-03 2011-09-20 Eli Lilly And Company Echinocandin/carbohydrate complexes
US6991800B2 (en) 2002-06-13 2006-01-31 Vicuron Pharmaceuticals Inc. Antifungal parenteral products
US7198796B2 (en) 2002-06-13 2007-04-03 Vicuron Pharmaceuticals Inc. Antifungal parenteral products

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AU5799096A (en) 1996-12-11
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ZA964011B (en) 1997-11-20
DE69624167T2 (de) 2003-02-13
DE69624167D1 (de) 2002-11-14
AR002104A1 (es) 1998-01-07
US5786325A (en) 1998-07-28
ATE225804T1 (de) 2002-10-15
EP0744407A3 (fr) 1998-05-20
EP0744407B1 (fr) 2002-10-09
EP0744407A2 (fr) 1996-11-27
IL118331A0 (en) 1996-09-12

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